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Questions and Answers
What is indicated by a straight line on a plot of steady-state concentrations versus doses?
What is indicated by a straight line on a plot of steady-state concentrations versus doses?
Which of the following describes non-linear pharmacokinetics?
Which of the following describes non-linear pharmacokinetics?
What can cause problems when adjusting doses for drugs that follow nonlinear kinetics?
What can cause problems when adjusting doses for drugs that follow nonlinear kinetics?
How does a two-fold increase in dosage affect steady-state concentration in drugs that follow linear pharmacokinetics?
How does a two-fold increase in dosage affect steady-state concentration in drugs that follow linear pharmacokinetics?
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What is indicated when the processes eliminating the drug from the body become saturated?
What is indicated when the processes eliminating the drug from the body become saturated?
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What is the result of a 50% increase in dose for drugs exhibiting linear pharmacokinetics?
What is the result of a 50% increase in dose for drugs exhibiting linear pharmacokinetics?
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What equation is often used to simulate the elimination of a drug by a saturable enzymatic process?
What equation is often used to simulate the elimination of a drug by a saturable enzymatic process?
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Which statement accurately characterizes linear pharmacokinetics?
Which statement accurately characterizes linear pharmacokinetics?
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What factors determine the volume of distribution (V)?
What factors determine the volume of distribution (V)?
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How does clearance affect the half-life (t1/2) of a drug?
How does clearance affect the half-life (t1/2) of a drug?
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At which concentration range is phenytoin considered potentially dangerous due to accumulation?
At which concentration range is phenytoin considered potentially dangerous due to accumulation?
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What is the relationship between the maintenance dose (MD) and the target steady-state serum concentration (Css) when Km is much greater than Css?
What is the relationship between the maintenance dose (MD) and the target steady-state serum concentration (Css) when Km is much greater than Css?
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What happens to the half-life of a drug when dosages are increased?
What happens to the half-life of a drug when dosages are increased?
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Which equation is used to compute the maintenance dose (MD) for a drug at steady state?
Which equation is used to compute the maintenance dose (MD) for a drug at steady state?
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What is the effect of repeated dosing every 12 hours for phenytoin at higher concentrations?
What is the effect of repeated dosing every 12 hours for phenytoin at higher concentrations?
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How does saturation of the enzyme system affect drug metabolism when Css is far below Km?
How does saturation of the enzyme system affect drug metabolism when Css is far below Km?
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What does the Michaelis constant (Km) represent in enzyme kinetics?
What does the Michaelis constant (Km) represent in enzyme kinetics?
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How is the clearance of a drug that follows Michaelis-Menten pharmacokinetics characterized?
How is the clearance of a drug that follows Michaelis-Menten pharmacokinetics characterized?
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In the equation Cl = Vmax/(Km + C), what happens to clearance (Cl) as the concentration (C) approaches Km?
In the equation Cl = Vmax/(Km + C), what happens to clearance (Cl) as the concentration (C) approaches Km?
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For phenytoin, what happens to the clearance as the steady-state concentration (Css) increases from 10 to 20 mg/L?
For phenytoin, what happens to the clearance as the steady-state concentration (Css) increases from 10 to 20 mg/L?
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What is a characteristic of drugs that exhibit saturable pharmacokinetics?
What is a characteristic of drugs that exhibit saturable pharmacokinetics?
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What does the term 'zero-order elimination' imply in drug metabolism?
What does the term 'zero-order elimination' imply in drug metabolism?
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If a drug has a high Vmax value, what does this indicate about its enzyme capacity?
If a drug has a high Vmax value, what does this indicate about its enzyme capacity?
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In the context of pharmacokinetics, what does the term 'saturable conditions' refer to?
In the context of pharmacokinetics, what does the term 'saturable conditions' refer to?
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What occurs when the therapeutic range for a drug is far above the Km value for the enzyme system that metabolizes the drug?
What occurs when the therapeutic range for a drug is far above the Km value for the enzyme system that metabolizes the drug?
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What type of pharmacokinetics occurs when the fraction of drug eliminated remains constant?
What type of pharmacokinetics occurs when the fraction of drug eliminated remains constant?
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What is indicated when a drug exhibits both first-order and zero-order pharmacokinetics?
What is indicated when a drug exhibits both first-order and zero-order pharmacokinetics?
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Which of the following drugs switches from first-order to zero-order pharmacokinetics at therapeutic concentrations?
Which of the following drugs switches from first-order to zero-order pharmacokinetics at therapeutic concentrations?
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What happens to the value of Km when the drug concentration is much higher than Km?
What happens to the value of Km when the drug concentration is much higher than Km?
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What pharmacokinetic behavior do most drugs display under normal therapeutic ranges?
What pharmacokinetic behavior do most drugs display under normal therapeutic ranges?
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In cases of drug overdose, what can happen to the pharmacokinetics of a drug?
In cases of drug overdose, what can happen to the pharmacokinetics of a drug?
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What happens to the rate of drug metabolism when the enzymes are completely saturated?
What happens to the rate of drug metabolism when the enzymes are completely saturated?
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What term describes pharmacokinetics where the elimination rate is affected by the drug concentration due to enzyme saturation?
What term describes pharmacokinetics where the elimination rate is affected by the drug concentration due to enzyme saturation?
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Which drug is an example of one that may exhibit saturable plasma protein binding?
Which drug is an example of one that may exhibit saturable plasma protein binding?
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What happens to drug concentrations above a certain level in saturable protein binding?
What happens to drug concentrations above a certain level in saturable protein binding?
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What is the primary characteristic of autoinduction of drug metabolism?
What is the primary characteristic of autoinduction of drug metabolism?
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Which parameter in the Michaelis-Menten equation represents the maximum rate of metabolism?
Which parameter in the Michaelis-Menten equation represents the maximum rate of metabolism?
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What is a significant challenge when dosing drugs that exhibit non-linear pharmacokinetics?
What is a significant challenge when dosing drugs that exhibit non-linear pharmacokinetics?
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According to the Michaelis-Menten formula, what does 'Km' represent?
According to the Michaelis-Menten formula, what does 'Km' represent?
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What occurs when the steady-state serum concentrations increase less than expected with dosage adjustments in certain drugs?
What occurs when the steady-state serum concentrations increase less than expected with dosage adjustments in certain drugs?
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Study Notes
Clinical Pharmacokinetics Lecture 3
- This lecture covers non-linear pharmacokinetics, discussing differences from linear pharmacokinetics, potential risks in dosing, and detection methods.
- Objectives include describing the differences between linear and nonlinear pharmacokinetics, discussing potential risks in dosing drugs with nonlinear kinetics, explaining how to detect nonlinear kinetics using AUC versus dose plots, applying relevant equations and graphical methods to calculate Vmax and Km parameters after multiple dosing, and describing the use of the Michaelis-Menten equation to simulate drug elimination via a saturable enzymatic process.
Linear versus Non-linear Pharmacokinetics
- Linear pharmacokinetics: Regardless of administration rate, if the rate of drug administration equals the removal rate, the amount of drug in the body reaches a constant value known as steady-state serum concentration (Css). A plot of Css versus dose yields a straight line indicating linear pharmacokinetics.
- Non-linear pharmacokinetics: In this case, the change in steady-state serum concentration (Css) is not proportional to the dose change. The plot of Css versus dose is not a straight line, implying the drug's elimination process becomes saturated at higher concentrations, impacting clearance.
Saturable Pharmacokinetics (Michaelis-Menten)
- Michaelis-Menten kinetics describe how drug elimination becomes saturated. This happens when the rate of metabolism is determined by the capacity of the enzyme system rather than the drug concentration.
- Key equation: V = (Vmax * S) / (Km + S), where:
- V is the initial reaction rate.
- Vmax is the maximum reaction rate.
- S is the substrate concentration (drug concentration).
- Km is the Michaelis constant, representing the substrate concentration at which the reaction rate is half of Vmax.
- This saturation can affect clearances and half-lives, making dosing more complex.
- For example, increasing the dose does not proportionally increase the elimination rate due to enzyme saturation.
- Important drugs showing saturable kinetics include phenytoin, salicylic acid, and theophylline; they have a Vmax, Km, and Css that need to be considered during dosing to avoid overdose.
- The volume of distribution (Vd) is unaffected by saturable metabolism and is determined by physiological volumes of blood and tissues and unbound drug concentrations in those compartments.
Clearance
- Clearance (CL) is not a constant in Michaelis-Menten kinetics but is concentration-dependent.
- Its formula: CL = Vmax / (Km + C)
- As concentration increases, clearance decreases as the enzyme approaches saturation.
- Thus, the half-life of the drug also increases as its concentration rises.
Half-life
- The half-life (t1/2) still relates to clearance and volume of distribution using the same formula as linear pharmacokinetics: t1/2 = 0.693/K.
- t1/2 = (0.693V)/CL
- Half-life changes with concentration changes due to the clearance's dose or concentration dependence. Increasing concentrations cause half-life (t1/2) to increase.
Other Factors
- Autoinduction: Certain drugs (e.g., carbamazepine) increase their own metabolism rate as the dose goes up, leading to less than proportional increases in steady-state concentrations.
- Mixed-order pharmacokinetics: Many drugs show first-order kinetics at low concentrations and zero-order kinetics at high concentrations. The concentration at which this change occurs is important. (e.g. phenytoin vs theophylline)
Clinical Correlations
- Many drugs display mixed-order pharmacokinetics, exhibiting first-order behavior at low and zero-order behavior at high concentrations.
- Understanding the concentration at which a drug switches from first to zero order is crucial for appropriate dosing and avoidance of overdosing (often because of drug accumulation).
Important Considerations
- Interpatient variability exists in Michaelis-Menten parameters, making precise dosing challenging.
- Although some drugs are metabolized in a linear manner at therapeutic levels, they can have saturable metabolism during excessive drug use.
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Description
This lecture focuses on non-linear pharmacokinetics, highlighting the distinctions from linear pharmacokinetics. Key topics include potential dosing risks, detection methods, and the application of the Michaelis-Menten equation. Gain insights into using AUC versus dose plots and calculating pharmacokinetic parameters.
